Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
Front Cell Infect Microbiol. 2013 Feb 12;3:3. doi: 10.3389/fcimb.2013.00003. eCollection 2013.
Lipopolysaccharide (LPS) is a component of the outer membrane of almost all Gram-negative bacteria and consists of lipid A, core sugars, and O-antigen. LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response. Most of what is known about how LPS is recognized by the TLR4-MD-2 receptor complex on animal cells has been studied using Escherichia coli lipid A, which is a strong agonist of TLR4 signaling. Recent work from several groups, including our own, has shown that several important pathogenic bacteria can modify their LPS or lipid A molecules in ways that significantly alter TLR4 signaling to NFκB. Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response. Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens. In this review, we provide an overview of lipid A variants from several human pathogens, how the basic structure of lipid A is recognized by mouse and human TLR4-MD-2 receptor complexes, as well as how alteration of this pattern affects its recognition by TLR4 and impacts the downstream immune response.
脂多糖（LPS）是几乎所有革兰氏阴性菌外膜的组成部分，由脂质 A、核心糖和 O 抗原组成。LPS 被宿主固有免疫细胞上的 Toll 样受体 4（TLR4）和 MD-2 识别，可信号激活转录因子 NFκB，导致产生引发和塑造适应性免疫反应的促炎细胞因子。关于 LPS 如何被 TLR4-MD-2 受体复合物在动物细胞上识别，人们已经通过研究大肠杆菌脂多糖（TLR4 信号的强激动剂）了解了大部分内容。最近，包括我们自己在内的几个研究小组的工作表明，几种重要的致病性细菌可以修饰它们的 LPS 或脂质 A 分子，从而显著改变 TLR4 信号向 NFκB 的传递。因此，人们假设脂质 A 变体的表达是病原体调节或逃避宿主免疫反应的一种机制。此外，已经表明，人源和鼠源 TLR4-MD-2 受体的氨基酸序列中的几个关键差异会改变识别这些脂质 A 变异的能力，这表明宿主对这些病原体的免疫反应具有特异性影响。在这篇综述中，我们概述了来自几种人类病原体的脂质 A 变体、脂质 A 的基本结构如何被鼠源和人源 TLR4-MD-2 受体复合物识别，以及这种模式的改变如何影响其被 TLR4 的识别并影响下游免疫反应。
